Stereochemically complex sp3-rich molecules represent privileged chemical scaffolds for the treatment of a broad range of human diseases, often with potent and specific biological activities. However, because these types of molecules are often challenging to prepare and modify, they have been underutilized in compound libraries for drug discovery. Therefore, the development of novel synthetic methods to access these structures in a general, efficient, and stereocontrolled manner is essential. The central hypothesis of this research proposal is that hydrogen bond donor catalysis using small molecule chiral thioureas is a general strategy for the preparation of highly enantioenriched molecules, which avoids potentially toxic transition metals and Lewis acids and obviates the requirement for functionality in the substrate that is capable of covalently interacting with a chiral catalyst. Instead, these catalysts mimic the active site of enzymes by utilizing hydrogen bonding and other non-covalent interactions to effect highly efficient and selective transformations without requiring the larger enzyme architecture. Specifically, this hypothesis will be tested in the development of the first highly enantioselective Prins-type cyclization reactions. These reactions, which involve the acid-catalyzed condensation of linear alkenols (or alkenylamines) and aldehydes followed by cyclization of an oxocarbenium/iminium intermediate, are a highly versatile synthetic strategy for the preparation of biologically prevalent oxygen- and nitrogen-containing aliphatic heterocycles, but have not been successfully rendered enantioselective using traditional asymmetric approaches. The proposed research will employ a cooperative catalysis approach by exploring chiral thiourea catalysts with functionality that is able to engage in cation-? interactions with the oxocarbenium/iminium intermediate in concert with Brnsted acid co-catalysts whose conjugate bases effectively bind to the thiourea to generate a tightly bound chiral ion pair that exerts significant control over the stereochemical outcome of the cyclization. With the establishment of a successful enantioselective method for the Prins and aza-Prins variants, this proposal will aim to 1) apply enantioselective Prins-type cyclizations to the synthesis of bioactive molecules, and 2) study the reaction mechanism and model catalyst-substrate interactions to elucidate the origin of enantioinduction. In particular, the synthetic ai of the proposed research will focus on introducing pharmacophoric moieties and maximizing the generality and structural diversity of the enantioselective transformations. The successful achievement of these specific aims would represent a significant practical and conceptual advance, solving an important synthetic problem and contributing to the utility and fundamental understanding of hydrogen bond donor catalysts. Moreover, this enabling synthetic method will allow biologically active aliphatic heterocycle-containing molecules to be prepared and modified efficiently for the development of diverse sp3-rich compound libraries in order to study and improve existing therapies and to discover new therapies for the treatment of human diseases.